Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis
Abstract Background Biliary Atresia (BA) is rare and genetically complex, and the pathogenesis is elusive. The disease course is variable and can represent heterogeneity, which hinders effective disease management. Deciphering the BA phenotypic variance is a priority in clinics and can be achieved b...
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| Format: | Article |
| Language: | English |
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BMC
2017-04-01
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| Series: | BMC Medical Genomics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12920-017-0259-0 |
| _version_ | 1818666983079542784 |
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| author | Guo Cheng Patrick Ho-Yu Chung Edwin Kin-Wai Chan Man-Ting So Pak-Chung Sham Stacey S. Cherny Paul Kwong-Hang Tam Maria-Mercè Garcia-Barceló |
| author_facet | Guo Cheng Patrick Ho-Yu Chung Edwin Kin-Wai Chan Man-Ting So Pak-Chung Sham Stacey S. Cherny Paul Kwong-Hang Tam Maria-Mercè Garcia-Barceló |
| author_sort | Guo Cheng |
| collection | DOAJ |
| description | Abstract Background Biliary Atresia (BA) is rare and genetically complex, and the pathogenesis is elusive. The disease course is variable and can represent heterogeneity, which hinders effective disease management. Deciphering the BA phenotypic variance is a priority in clinics and can be achieved by the integrative analysis of genotype and phenotype. We aim to explore the BA phenotypic features and to delineate the source of its variance. Methods The study is a cross-sectional observational study collating with case/control association analysis. One-hundred-and-eighty-one type III non-syndromic BA patients and 431 controls were included for case–control association tests, including 89 patients (47.19% males, born June 15th, 1981 to September 17th, 2007) have detailed clinical records with follow-up of the disease course (median ~17.2 years). BA-association genes from the genome-wide gene-based association test on common genetic variants (CV) and rare copy-number-variants (CNVs) from the genome-wide survey, the later comprise only CNVs > 100 kb and found in the BA patients but not in the local population (N = 1,381) or the database (N = 11,943). Hereby comorbidity is defined as a chronic disease that affects the BA patients but has no known relationship with BA or with the BA treatment. We examined genotype-phenotype correlations of CNVs, connectivity of these novel variants with BA-associated CVs, and their role in the BA candidate gene network. Results Of the 89 patients, 41.57% have comorbidities, including autoimmune-allergic disorders (22.47%). They carried 29 BA-private CNVs, including 3 CNVs underpinning the carriers’ immunity comorbidity and one JAG1 micro-deletion. The BA-CNV-intersected genes (N = 102) and the CV-tagged genes (N = 103) were both enriched with immune-inflammatory pathway genes (FDR q < 0.20), and the two gene sets were interconnected (permutation p = 0.039). The molecular network representing CVs and rare-CNV association genes fit into a core/periphery structure, the immune genes and their related modules are found at the coherence core of all connections, suggesting its dominant role in the BA pathogenesis pathway. Conclusions The study highlights a patient-complexity phenomenon as a novel BA phenotypic feature, which is underpinned by rare-CNVs that biologically converge with CVs into the immune-inflammatory pathway and drives the BA occurrence and the likely BA association with immune diseases in clinics. |
| first_indexed | 2024-12-17T06:13:11Z |
| format | Article |
| id | doaj.art-98007cc650c84dbca87933c317603a91 |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-12-17T06:13:11Z |
| publishDate | 2017-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj.art-98007cc650c84dbca87933c317603a912022-12-21T22:00:35ZengBMCBMC Medical Genomics1755-87942017-04-011011910.1186/s12920-017-0259-0Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysisGuo Cheng0Patrick Ho-Yu Chung1Edwin Kin-Wai Chan2Man-Ting So3Pak-Chung Sham4Stacey S. Cherny5Paul Kwong-Hang Tam6Maria-Mercè Garcia-Barceló7Department of Surgery, 1/F Hong Kong Jockey Club Building for Interdisciplinary ResearchDepartment of Surgery, 1/F Hong Kong Jockey Club Building for Interdisciplinary ResearchDepartment of Surgery, the Chinese University of Hong KongDepartment of Surgery, 1/F Hong Kong Jockey Club Building for Interdisciplinary ResearchDepartment of Psychiatry, The University of Hong KongDepartment of Psychiatry, The University of Hong KongDepartment of Surgery, 1/F Hong Kong Jockey Club Building for Interdisciplinary ResearchDepartment of Surgery, 1/F Hong Kong Jockey Club Building for Interdisciplinary ResearchAbstract Background Biliary Atresia (BA) is rare and genetically complex, and the pathogenesis is elusive. The disease course is variable and can represent heterogeneity, which hinders effective disease management. Deciphering the BA phenotypic variance is a priority in clinics and can be achieved by the integrative analysis of genotype and phenotype. We aim to explore the BA phenotypic features and to delineate the source of its variance. Methods The study is a cross-sectional observational study collating with case/control association analysis. One-hundred-and-eighty-one type III non-syndromic BA patients and 431 controls were included for case–control association tests, including 89 patients (47.19% males, born June 15th, 1981 to September 17th, 2007) have detailed clinical records with follow-up of the disease course (median ~17.2 years). BA-association genes from the genome-wide gene-based association test on common genetic variants (CV) and rare copy-number-variants (CNVs) from the genome-wide survey, the later comprise only CNVs > 100 kb and found in the BA patients but not in the local population (N = 1,381) or the database (N = 11,943). Hereby comorbidity is defined as a chronic disease that affects the BA patients but has no known relationship with BA or with the BA treatment. We examined genotype-phenotype correlations of CNVs, connectivity of these novel variants with BA-associated CVs, and their role in the BA candidate gene network. Results Of the 89 patients, 41.57% have comorbidities, including autoimmune-allergic disorders (22.47%). They carried 29 BA-private CNVs, including 3 CNVs underpinning the carriers’ immunity comorbidity and one JAG1 micro-deletion. The BA-CNV-intersected genes (N = 102) and the CV-tagged genes (N = 103) were both enriched with immune-inflammatory pathway genes (FDR q < 0.20), and the two gene sets were interconnected (permutation p = 0.039). The molecular network representing CVs and rare-CNV association genes fit into a core/periphery structure, the immune genes and their related modules are found at the coherence core of all connections, suggesting its dominant role in the BA pathogenesis pathway. Conclusions The study highlights a patient-complexity phenomenon as a novel BA phenotypic feature, which is underpinned by rare-CNVs that biologically converge with CVs into the immune-inflammatory pathway and drives the BA occurrence and the likely BA association with immune diseases in clinics.http://link.springer.com/article/10.1186/s12920-017-0259-0Copy number variantRare complex diseaseGenotype-phenotype correlationNetwork |
| spellingShingle | Guo Cheng Patrick Ho-Yu Chung Edwin Kin-Wai Chan Man-Ting So Pak-Chung Sham Stacey S. Cherny Paul Kwong-Hang Tam Maria-Mercè Garcia-Barceló Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis BMC Medical Genomics Copy number variant Rare complex disease Genotype-phenotype correlation Network |
| title | Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis |
| title_full | Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis |
| title_fullStr | Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis |
| title_full_unstemmed | Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis |
| title_short | Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis |
| title_sort | patient complexity and genotype phenotype correlations in biliary atresia a cross sectional analysis |
| topic | Copy number variant Rare complex disease Genotype-phenotype correlation Network |
| url | http://link.springer.com/article/10.1186/s12920-017-0259-0 |
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